Diabetes is a group of heterogeneous chronic disorders characterised by hyperglycaemia due to relative or absolute insulin deficiency. Two major categories of diabetes are recognised according to aetiology and clinical presentation, type 1 diabetes and type 2 diabetes. More than 90% cases are accounted for by type 2 diabetes. Regional and ethnic differences in diabetes incidence and prevalence exist.
Type 1 diabetes is one of the most common chronic childhood disease in developed nations but occurs at all ages. Type 1 diabetes is caused by autoimmune destruction of pancreatic islet beta-cells resulting in the absolute loss of insulin production. Treatment demands the administration of exogenous insulin. Type 1 diabetes is associated with a high rate of complications normally occurring at young ages placing a considerable burden on the individual and the society.
In a healthy individual, insulin is secreted by the pancreas in a highly controlled fashion to maintain the plasma glucose concentration within a narrow physiological range. In type 1 diabetes, insulin is delivered exogenously to mimic the basal and postprandial insulin needs. The standard therapy is based on multiple insulin injections using a combination of short and long acting insulin analogues supported by blood glucose self-monitoring (“Standards of Medical Care in Diabetes,” Diabetes Care, 28: S4-S36, 2005). Treatment by the continuous subcutaneous insulin infusion (CSII), i.e. using insulin pumps, is on the rise (J. Pickup and H. Keen, “Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes,” Diabetes Care, 25: 593-598, 2002).
The last two decades have witnessed unprecedented technological progress in the development of continuous glucose sensors (e.g. as described in EP0939602) resulting in the first generation of commercial glucose monitors (D. C. Klonoff, “Continuous Glucose Monitoring: Roadmap for 21st century diabetes therapy,” Diabetes Care, 28: 1231-1239, 2005). This has fuelled the development of prototypes of a closed-loop system based on combination of a continuous monitor, a control algorithm, and an insulin pump (R. Hovorka. “Continuous glucose monitoring and closed-loop systems,” Diabetic Med. 23 (1):1-12, 2006). These systems are normally termed an artificial pancreas.
As part of the artificial pancreas, the continuous glucose monitor could be an implantable or extracorporeal device and based on a minimally or non-invasive technology (D. C. Klonoff, “Continuous Glucose Monitoring: Roadmap for 21st century diabetes therapy,” Diabetes Care, 28: 1231-1239, 2005). Generally, the implantable sensors are projected to have a lifespan of several months to years lifetime the non-implantable devices have, at present, a lifetime of one half day to several days.
Similarly, the insulin pump can be implanted or extracorporeal. The implantable pump normally delivers insulin intraperitoneally whereas the extracorporeal insulin pump delivers insulin subcutaneously.
The control algorithm can be implemented on a separate device, a patient monitor, or on the same platform as the insulin pump. The communication between the devices can be achieved using wire or wireless technologies. The latter are becoming prevalent for the transfer of data from insulin pumps onto diabetes management systems. Integrated systems exist which allow wireless transfer of data between glucose meters and insulin pumps such as the “all-in-one” CozMore™ Insulin Technology System (Smiths Medical MD, Inc, MN) or the Medtronic MiniMed Paradigm REAL-Time system (Northridge Calif., USA).
A wide spectrum of control algorithms has been proposed to titrate insulin in a closed-loop fashion, see a review by Parker et al (Parker R S, Doyle F J, III, Peppas N A. The intravenous route to blood glucose control. IEEE Eng Med Biol Mag 2001; 20(1): 65-73). For a clinical evaluation, two main categories have been employed, classical feedback control embodied in the proportional-integral-derivative (PID) controller, and model predictive control (MPC).
The principles of feedback control can be exemplified using the PID controller. The controller continuously adjusts the insulin infusion rate (IIR) by assessing glucose excursions from three viewpoints, the departure from the target glucose (the proportional component), the amount of time when glucose is different from the target glucose (the integral component), and the change in ambient glucose (the derivative component). IIR is computed as
  IIR  =                    K        P            ⁡              (                  G          -                      G            t                          )              +                  K        I            ⁢              ∫                  (                      G            -                          G                              t                ⁢                                                                                                )                      +                  K        D            ⁢                        ⅆ          G                          ⅆ          t                    where KP, KI, and KD represent weights (gains) given to the proportional, integral, and derivative components, and G and Gt represent ambient and target glucose levels, respectively.
Tuning of the controller corresponds to the determination of constants KP, KI and KD. This can be achieved by an off-line assessment using, for example, pharmacokinetics modelling, or on-line using adaptive techniques. The constants can also be estimated from a subject's daily dose while the ratios between the constants remain the same.
The model predictive control is at the forefront of the recent research with contributions, for example, by Parker et al (Parker R S, Doyle F J, III, Peppas N A. A model-based algorithm for blood glucose control in type I diabetic patients. IEEE Trans Biomed Eng 1999; 46(2): 148-157), Lynch and Bequette (Lynch S M, Bequette B W. Estimation-based model predictive control of blood glucose in type I diabetics: A simulation study. Proc of the IEEE 27th Annual Northeast Bioengineering Conference 2001; 79-80), Trajanoski at al (Trajanoski Z, Wach P. Neural predictive controller for insulin delivery using the subcutaneous route. IEEE Trans Biomed Eng 1998; 45(9): 1122-1134), and Hovorka et al (Hovorka R, Canonico V, Chassin L J, Haueter U, Massi-Benedetti M, Orsini-Federici M et al. Non-linear model predictive control of glucose concentration in subjects with type 1 diabetes. Physiol Meas 2004; 25(4): 905-920). The MPC approach is most suitable for systems with long delays and open-loop characteristics and therefore well suited for the sc-sc approach with meal announcement.
The vital ingredient of the model predictive control is a model linking insulin delivery and possibly meal ingestion to glucose excursions. This can be a physiological model representing fundamental glucoregulatory processes or a “black-box” model disregarding the physiological insights but learning the insulin-glucose relationships using pattern recognition techniques. Both approaches can benefit from a wide range of models of the glucoregulatory system.
The development of the MPC controller consists of selecting a suitable model, obtaining model parameters, and deciding on other elements such as the length of the prediction window and the form of the target trajectory. Adaptive techniques allow model parameters to be individualised either off- or on-line.
Apart from being used as part of a closed-loop system, continuous glucose monitoring can also be used on retrospective basis to optimise insulin delivery in an open-loop algorithm-based treatment modification (R. Hovorka. Management of diabetes using adaptive control. Int. J. Adapt. Control 19 (5):309-326, 2005; C. C. Palerm, H. Zisser, W. C. Bevier, L. Jovanovic, and F. J. Doyle, III. Prandial insulin dosing using run-to-run control: application of clinical data and medical expertise to define a suitable performance metric. Diabetes Care 30 (5):1131-1136, 2007). It can also be used by the patient to deliver a correction insulin bolus, to modify temporarily the delivery of insulin via the insulin pump, to warn of impeding too low or too high glucose level, or to take other diabetes management actions.
In summary, continuous glucose monitor can be used as a part of a closed-loop system with automated insulin delivery or as a part of open-loop system for retrospective data evaluation or real-time sporadic management interventions initiated by the patient or his/her career.